Primary Immunodeficiencies: A&Nbsp;Rapidly Evolving Story

Primary immunodeﬁciencies: A rapidly evolving story

Nima Parvaneh, MD,a,b Jean-Laurent Casanova, MD, PhD,c,d Luigi Daniele Notarangelo, MD, PhD,e,f and Mary Ellen Conley, MDg,h Tehran, Iran, New York, NY, Paris, France, Boston, Mass, and Memphis, Tenn

The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the Abbreviations used biology of the immune response. New achievements in this field ADAM17: A disintegrin and metalloproteinase 17 have been possible in light of collaborative studies; attention BCR: B-cell receptor paid to new phenotypes, infectious and otherwise; improved EV: Epidermodysplasia verruciformis immunologic techniques; and use of exome sequencing HHV6: Human herpesvirus 6 HPS: Hermansky-Pudlak syndrome technology. The International Union of Immunological Societies HPV: Human papilloma virus Expert Committee on PIDs recently reported on the updated HSE: Herpes simplex virus encephalitis classification of PIDs. However, new PIDs are being discovered HSV1: Herpes simplex virus 1 at an ever-increasing rate. A series of 19 novel primary defects ICA: Isolated congenital asplenia of immunity that have been discovered after release of the ICL: Idiopathic CD41 lymphopenia International Union of Immunological Societies report are IL-36Ra: IL-36 receptor antagonist discussed here. These new findings highlight the molecular ISG15: Interferon-stimulated gene 15 pathways that are associated with clinical phenotypes and IUIS: International Union of Immunological Societies suggest potential therapies for affected patients. (J Allergy Clin LCK: Lymphocyte-specific protein tyrosine kinase Immunol 2013;131:314-23.) LRBA: LPS-responsive beige-like anchor MCM4: Minichromosome maintenance complex component 4 Key words: Primary immunodeficiencies, combined immunodefi- MSMD: Mendelian susceptibility to mycobacterial disease ciencies, well-defined syndromes with immunodeficiency, predomi- MST: Mammalian Ste20-like kinase k nantly antibody defects, defects of immune dysregulation, NEMO: NF- B essential modulator NF-kB: Nuclear factor kB congenital defects of phagocytes, defects in innate immunity, autoin- NK: Natural killer flammatory disorders, mutation detection PI3K: Phosphoinositide 3-kinase PID: Primary immunodeficiency Discuss this article on the JACI Journal Club blog: www.jaci- PLCg2: Phospholipase Cg2 online.blogspot.com. RHOH: Ras homolog gene family member H TBK1: TANK-binding kinase 1 TCR: T-cell receptor Known primary immunodeficiencies (PIDs) include individu- TLR3: Toll-like receptor 3 ally rare but collectively diverse genetic defects that influence TRIF: Toll/IL-1 receptor domain–containing adaptor inducing IFN-b UNC119: Uncoordinated 119 From athe Pediatric Infectious Diseases Research Center and bthe Research Center for WASP: Wiskott-Aldrich syndrome protein Immunodeficiencies, Children’s Medical Center, Tehran University of Medical WIP: WASP-interacting protein Sciences, Tehran; cSt Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York; dthe Laboratory of Human Ge- netics of Infectious Diseases, Necker Branch, Necker Medical School, University Paris Descartes and INSERM U980, Paris; ethe Division of Immunology and fthe Manton Center for Orphan Disease Research, Children’s Hospital Boston, Harvard Medical the development, function, or both of immunity. Taken in a broad School, Boston; gthe Department of Pediatrics, University of Tennessee College of sense, these disorders encompass both the hematopoietic and h Medicine, Memphis; and Le Bonheur Children’s Hospital, Memphis. nonhematopoietic arms of host defense. They result in a wide Disclosure of potential conflict of interest: J.-L. Casanova has received grants from the National Institutes of Health (NIH); has been a consultant for Pfizer, GlaxoSmith- range of clinical symptoms, including but not limited to suscep- Kline, NovImmune, Biogenldec, Merck, and Sanofi-Aventis; and has grants/grants tibility to infections, autoimmunity, inflammation, allergy, and 1 pending from Pfizer and Merck. L. D. Notarangelo is a board member for the Immune malignancy. Significant progress in the field has recently accel- Disease Institute, is employed by Children’s Hospital Boston, has grants/grants erated thanks to collaborative work around the world; improved pending with the NIH, the March of Dimes, and the Jeffrey Modell Foundation; techniques to analyze leukocyte subsets; attention paid to new and has received payment for lectures, including service on speakers’ bureaus for the WAS foundation. M. E. Conley is employed by the University of Tennessee, phenotypes, such as infections selectively caused by certain 2 has received grants/grants pending from the NIH and the March of Dimes, has re- pathogens in otherwise healthy children ; and use of high- ceived payment for lectures from the Immune Deficiency Foundation, and is receiving throughput next-generation sequencing technology (eg, whole- royalties from the Southern Bio for monoclonal antibodies. N. Parvaneh declares no exome sequencing).3 The International Union of Immunological relevant conflicts of interest. Received for publication October 2, 2012; revised November 6, 2012; accepted for pub- Societies (IUIS) Expert Committee on PIDs published the bien- lication November 29, 2012. nial update of the classification of PIDs in a recent article dated 4 Corresponding author: Nima Parvaneh, MD, Pediatric Infectious Diseases Research Cen- November 2011. However, the continuously growing number ter, Children’s Medical Center, 62 Gharib St, 14194 Tehran, Iran. E-mail: nparvaneh@ and variety of PIDs make this type of classification difficult tums.ac.ir. and perhaps calls for a revised approach.5,6 In this review we 0091-6749/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology focus on the 19 new PIDs that appeared in the literature after http://dx.doi.org/10.1016/j.jaci.2012.11.051 the release of the last IUIS report. Some of these reports include

314 J ALLERGY CLIN IMMUNOL PARVANEH ET AL 315 VOLUME 131, NUMBER 2 only a single case, making it difficult to confidently predict the there is a clear keratinocyte phenotype13 but only mild T-cell clinical phenotype; however, each new disorder provides valu- anomalies in EVER-deficient patients.14 A recent study explored able insights into the pathways that normally ensure host defense the genetic basis of an EV-like phenotype in 2 French siblings from environmental challenges while not harming the host. We with persistent cutaneous EV-HPV infections and other clinical classify these new PIDs according to the latest IUIS classi- manifestations, including bronchopulmonary disease and Burkitt fication (Table I). lymphoma in one of them, indicating that the phenotypic spec- trum of the disease is not restricted to susceptibility to HPV.15 Therefore this condition is related to but distinct from EV. The COMBINED IMMUNODEFICIENCIES patients were homozygous for a nonsense allele of the Ras T-cell receptor a gene mutation: T-cell receptor ab1 homolog gene family member H (RHOH), which encodes an T-cell depletion atypical Rho GTPase (RHOH) expressed predominantly in he- T cells comprise 2 distinct lineages that express either ab or gd matopoietic cells. RHOH is crucial for pre-TCR and TCR signal- T-cell receptor (TCR) complexes that perform different tasks in ing and has a role during b-selection and positive selection in the immune responses. During T-cell maturation, the precise order thymus.16,17 The patients displayed a lack of circulating naive and efficacy of TCR gene rearrangements determine the fate of T cells, a lower than normal proportion of skin-homing b71 the cells.7 Productive b-chain gene rearrangement produces a pre- T cells, and impaired TCR signaling. The combination of these TCR on the cell surface in association with pre-Ta invariant T-cell defects might explain the pathogenesis of susceptibility peptide (b-selection). Pre-TCR signals promote a-chain recombi- to cutaneous EV-HPVs. EV-like features were also recently nation and transition to a double-positive stage (CD41CD81).8 reported in a child with mammalian Ste20-like kinase (MST) This is the prerequisite for central tolerance achieved through pos- 1 deficiency (described below).18 itive and negative selection of thymocytes. Additional insight into the development of TCRab1 T cells was provided by the characterization of 2 patients from 2 unrelated Pakistani families who had the MST1 deficiency: Loss of naive T cells same homozygous mutation in the TCRa constant (TRAC)gene New insight into the role of MST1 as a critical regulator of and shared increased susceptibility to infections, autoimmunity, T-cell homing and function was provided by the characterization and profound T-cell proliferative impairments but apparently had of 8 patients from 4 unrelated families who had homozygous normal antibody responses.9 One of the cases showed predisposi- nonsense mutations in STK4, the gene encoding MST1.18-20 tion to herpes virus infections (including protracted varicella zoster MST1 was originally identified as an ubiquitously expressed and chronic EBV/HHV6 viremia) and chronic lung disease. In ad- kinase with structural homology to yeast Ste20.21 MST1 is the dition to immunodeficiency, both children had evidence of immune mammalian homolog of the Drosophila Hippo protein, control- dysregulation with a combination of eosinophilia, vitiligo, alopecia ling cell growth, apoptosis, and tumorigenesis.22 It has both areata, autoimmune hemolytic anemia, eczema, and the presence of proapoptotic and antiapoptotic functions.19 Clinically, the patients autoantibodies. T cells from affected subjects were devoid of sur- had recurrent bacterial, viral, and candidal infections; lymphope- face expression of the TCRab complex; all existing CD31 Tcells nia; intermittent neutropenia; EBV-driven lymphoproliferation; expressed TCRgd. Both patients were successfully treated with lymphoma; autoimmune cytopenias; and subtle cardiac anomalies. matched sibling bone marrow transplants. This study is of interest Of note is the development of HPV (both EV-HPV and non- because it is the first pure TCRab1 T-cell immunodeficiency, al- EV-HPV) infections in 3 of the patients.18,19 MST1-deficient lowing a fine definition of the role of this major cell lineage. Previ- patients demonstrated hypergammaglobulinemia and variable ously described disorders affected all T-cell lineages alone or in humoral responses. However, B-cell numbers (especially memory combination with B-cell or natural killer (NK) cell deficits. This ex- B-cell numbers) were significantly reduced in one report.19 Periph- periment confirms that gd T cells alone cannot ensure adequate host eral T cells displayed markedly impaired survival/proliferation to defense. It would be interesting to identify patients with a selective mitogens and antigens, a response that worsened with time.20 gd T-cell deficiency because the exact role of these T cells remains Moreover, the T-cell compartment showed a restricted TCR reper- 1 unknown. toire and a severe reduction in circulating naive (CD45RA )cell numbers. Together with RHOH deficiency, MST1 deficiency seems to affect naive T-cell development and homing, predispos- Ras homolog gene family member H deficiency: ing to various infections in affected subjects. Loss of naive T cells and persistent human papilloma virus infections Human papilloma viruses (HPVs) are double-stranded DNA Lymphocyte-specific protein tyrosine kinase viruses with a tropism for keratinocytes, causing chronic epi- deficiency: T-cell deficiency with CD41 lymphopenia thelial lesions that can progress to cancer.10 Susceptibility to Defects in pre-TCR– and TCR-mediated signaling lead to HPV infection can be genetically determined, as seen in epider- aberrant T-cell development and function (Fig 1). One of the ear- modysplasia verruciformis (EV). EV is characterized by early liest biochemical events occurring after engagement of the (pre)- development of widespread, refractory flat warts and pityriasis- TCR is the activation of lymphocyte-specific protein tyrosine like lesions and occasional development of skin carcinomas kinase (LCK), a member of the SRC family of protein tyrosine caused by certain types of HPV, called EV-HPV (or b-HPV kinases.23,24 This kinase then phosphorylates immunoreceptor types), in otherwise healthy subjects.11 Mutations in EVER1 or tyrosine-based activation motifs of intracellular domains of EVER2 have been identified in most but not all patients with CD3 subunits. Phosphorylated immunoreceptor tyrosine-based EV.12 To date, the exact mechanisms leading to persistent activation motifs recruit z-chain associated protein kinase of EV-HPV infections in EVER-deficient patients are unknown; 70 kDa, which, after being phosphorylated by LCK, is 316 PARVANEH ET AL J ALLERGY CLIN IMMUNOL FEBRUARY 2013

TABLE I. Novel PID genes and their phenotypes Gene Protein Inheritance Phenotype Combined immunodeficiencies TRAC TCRa AR TCRab1 T-cell deficiency, viral infections, autoimmunity RHOH RHOH AR Loss of naive T cells, HPV infection STK4 MST1 AR Loss of naive T cells, EBV infection, HPV infection, autoimmunity LCK LCK AR T-cell deficiency, CD41 lymphopenia UNC119 UNC119 AD, dominant negative ICL Well-defined syndromes with immunodeficiency WIPF1 WIP AR Wiskott-Aldrich syndrome-like PLCG2 Phospholipase Cg2 AD, dominant negative Cold urticaria, humeral deficiency, autoimmunity, atopy (S707Y) AD, hypermorphic Autoinflammatory syndrome (deletions) Predominantly antibody defects PIK3R1 p85a subunit of PI3K AR Agammaglobulinemia, absent B cells CD21 CD21 AR Hypogammaglobulinemia LRBA LRBA AR Hypogammaglobulinemia, autoimmunity, colitis Defects of immune dysregulation PLDN Pallidin AR HPS type 9, albinism, immunodeficiency CD27 CD27 AR EBV-associated lymphoproliferation, hypogammaglobulinemia Congenital defects of phagocyte number, function, or both ISG15 ISG15 AR MSMD Defects in innate immunity NKX2-5 NKX2-5 AD, dominant negative ICA TRIF TRIF AR Herpes simplex encephalitis TBK1 TBK1 AD, dominant negative (G159A), Herpes simplex encephalitis haploinsufficiency (D50A) MCM4 MCM4 AR NK cell deficiency, infection with herpesviruses, growth retardation, and adrenal insufficiency Autoinflammatory disorders ADAM17 ADAM17 AR Inflammatory skin and bowel disease, high IL-1 and IL-6 production IL36RN IL-36Ra AR Generalized pustular psoriasis

responsible for activation of critical downstream events. Major importance of LCK for the development of a normal T-cell rep- consequences include activation of the membrane-associated ertoire and also maintenance of central and peripheral T-cell enzyme phospholipase Cg1, activation of the mitogen-activated tolerance. protein kinase, nuclear translocation of nuclear factor kB (NF- kB), and Ca21/Mg21 mobilization. Through these pathways, LCK controls T-cell development and activation.25 In mice lack- Uncoordinated 119 deficiency: Idiopathic CD41 ing LCK, T-cell development in the thymus is profoundly lymphopenia blocked at an early double-negative stage.26 Although 3 cases Idiopathic CD41 lymphopenia (ICL) is a very heterogeneous of combined immunodeficiencies with altered LCK protein clinical entity that is defined, by default, by persistent CD41 expression had been reported in human subjects, the molecular T-cell lymphopenia (<300 cells/mL or <20% of total T cells) in defects at the genomic level were not documented.27-29 Recently, the absence of HIV infection or any other known cause of immu- autosomal recessive LCK deficiency was described as the cause nodeficiency.31 The few studies examining the pathogenesis of of profound T-cell immunodeficiency and immune dysregula- ICL suggest that in some patients accelerated apoptosis and tion.30 A French infant presented with early-onset protracted di- diminished proliferative capacity are partly due to disturbed arrhea, recurrent respiratory tract infections, failure to thrive, TCR signaling.32,33 Uncoordinated 119 (UNC119), an activator autoimmune thrombocytopenia, and skin/mucosal inflammatory of LCK, delivers LCK to the plasma membrane through an endo- disorders. Laboratory studies in the affected patient showed somal route and initiates the enzymatic activity of LCK on TCR CD41 T-cell lymphopenia and low Treg cell numbers. The resid- stimulation.34,35 Through LCK, UNC119 regulates some T-cell ual T lymphocytes had an oligoclonal T-cell repertoire and ex- functions, including immunologic synapse formation, prolifera- hibited a severe TCR signaling defect, with only weak tyrosine tion, and differentiation into effector cells.34-37 Recently, a heter- phosphorylation signals and no Ca21 mobilization after TCR ozygous dominant-negative missense mutation (V22G) of stimulation. Moreover, the patient’s T cells were resistant to UNC119 was reported in a patient with ICL.38 The patient was activation-induced cell death. She was found to have a homozy- a 32-year-old woman with a history of recurrent respiratory tract gous missense mutation of the LCK gene (c.1022T>C; L341P) infections, persistent fungal infections of the skin and nails, recur- resulting from maternal uniparental disomy. Anti-TNF therapy rent shingles, and oral herpes simplex lesions. The patient’s cells was partially effective in treating the serositis and skin inflamma- showed reduced response to TCR stimulation, with impairment in tion. She underwent matched unrelated hematopoietic stem cell LCK localization/activation resulting in decreased cell prolifera- transplantation at 30 months, but unfortunately, she died of post- tion. Transduction of the mutant UNC119 but not wild-type transplantation veno-occlusive disease. This study highlights the UNC119 into normal T cells reproduced the signaling and J ALLERGY CLIN IMMUNOL PARVANEH ET AL 317 VOLUME 131, NUMBER 2

FIG 1. TCR signaling. Multiple signal transduction pathways are stimulated through the TCR. These pathways collectively activate transcription factors that organize T-cell survival, proliferation, differentiation, homeostasis, and migration. Mutant molecules in patients with TCR-related defects are indicated in red. AP1, Activator protein 1; BCL10, B-cell lymphoma/leukemia 10; CARMA, CARD-containing MAGUK protein; DAG, diacylglycerol; ER, endoplasmic reticulum; FOXO, forkhead box O; GAD, GRB2-related adaptor protein; IKK,IkB kinase; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; LAT, linker of activated T cells; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NCK, noncatalytic region of tyrosine kinase adaptor protein; NFAT, nuclear factor of activated T cells; PDK, phosphoinositide-dependent kinase; PIP2, phosphatidyl inositol bisphosphate; PKB, protein kinase B; PKCu, protein kinase C u; RASGRP, RAS guanyl nucleotide–releasing protein; SLP-76, SH2 domain–containing leukocyte protein of 76 kDa; STIM1, stromal interaction molecule 1; ZAP70, z-chain associated protein kinase of 70 kDa. proliferation defects, confirming the inhibitory function of G22V patient displayed some immune abnormalities that have not mutation. These findings shed light on the molecular mechanisms been documented in patients with WAS. They include impaired for a subset of patients with ICL. T-cell response to IL-2, complete failure to proliferate in response to TCR ligation with anti-CD3, and complete abrogation of T-cell chemotaxis.41-43 Moreover, the mean platelet volume was normal in the patient, as seen in WIP-deficient mice.44 Unrelated cord WELL-DEFINED SYNDROMES WITH blood transplantation was performed at 4.5 months, and the child IMMUNODEFICIENCY is now doing well at age 21 months. This study is interesting Wiskott-Aldrich syndrome protein–interacting because it reports the first autosomal recessive form of WAS, protein deficiency: Wiskott-Aldrich syndrome-like one of the most emblematic X-linked recessive PIDs and arguably phenotype one of the first PIDs described, first by Wiskott in 193745 and then In hematopoietic cells Wiskott-Aldrich syndrome protein again by Aldrich in 1954.46 (WASP) is stabilized through forming a complex with WASP- interacting protein (WIP).39 A female Moroccan infant presented in early infancy with recurrent infections, eczema, thrombocytopenia, T-cell lymphopenia, and decreased NK cell function rem- Phospholipase Cg2 gain-of-function mutations: iniscent of WAS.40 Despite normal WAS sequence and mRNA Cold urticaria, immunodeficiency, and expression levels, WASP was not detected in the patient’s cells, autoimmunity/autoinflammatory suggesting WASP protein degradation caused by the absence of This is a unique phenotype, sharing features of antibody WIP. Further studies showed that WIP could not be detected in deficiency, autoinflammatory diseases, and immune dysregula- the patient’s T-cell blasts, and a homozygous nonsense mutation tory disorders, making its classification difficult. Two recent (S434X) was detected in WIPF1, which encodes WIP. Despite studies validated the pleiotropy of genetic alterations in the same clinical similarities with patients with WAS, the WIP-deficient gene.47,48 In the first study genomic deletions in PLCG2 were 318 PARVANEH ET AL J ALLERGY CLIN IMMUNOL FEBRUARY 2013 detected in 3 distinct families with a dominantly inherited syn- complications, including colitis, as a teenager.52 PI3Ks are a drome of cold urticaria and variable immune dysregulation.47 broadly expressed group of enzymes that respond to extracellular PLCG2 encodes phospholipase Cg2 (PLCg2), a signaling mole- signals to activate a variety of cellular functions.53 Although the cule expressed in B cells, NK cells, mast cells, and platelets. mutation did not affect the expression of p50a and p55a, the other PLCg transmits information from activated receptors to down- regulatory subunits encoded by PIK3R1, it did result in a marked stream signal cascades by triggering receptor-mediated Ca21 en- decrease in levels of p110d, the catalytic subunit of PI3K. The try.49,50 Cold urticaria occurred in all 27 affected subjects. developmental arrest in the patient was at the pro–B-cell stage, Interestingly, skin test results were positive for evaporative cool- earlier than that seen in patients with defects in the BCR signaling ing but negative on ice-cube and cold-water immersion. Other pathway.51 The extracellular signal that requires activation of the variable manifestations included atopy, sinopulmonary infec- PI3K pathway at this early stage of development is unknown; tions, autoimmune diseases, and granulomatous rashes in order however, it was noted that the chemokine CXCR4 transduces of frequency. Laboratory findings were also variable and included through PI3K54 and that defects in CXCR4 in mice cause a similar low serum IgM and IgA levels in some patients, diminished num- block in B-cell development.55 The patient had neutropenia at the bers of circulating CD191 B cells and switched memory B cells, time of diagnosis that was not seen during follow-up evaluations. and low NK cell numbers, whereas IgE levels were increased in Patients with early defects of B-cell development might present most of the subjects. The C-terminal SH2 deletions in PLCg2, with neutropenia before they are started on gammaglobulin which were seen in all 3 families, resulted in the failure of auto- replacement.56-58 Mice with p85a deficiency show a wide range inhibition and caused constitutive phospholipase activity when of defects, including a B-cell defect similar to that seen in mice transfected into COS7 cells.47 Paradoxically, B cells and NK cells with mutations in Btk, hypersensitivity to insulin, defective plate- clearly had decreased PLCg2-dependent signaling and function; let function, and abnormal mast cell development.59,60 In con- the exact mechanisms are not yet clear. Affected mast cells trast, in human subjects the absence of p85a results in a severe showed increased mast cell degranulation at cold temperatures isolated defect in development of early stages of B lineage cells without receptor stimulation, indicating that the altered function without associated findings. of mutant PLCg2 was the cause of cold urticaria. Another study by the same research group defined a hypermorphic dominant mutation within PLCG2 (p.Ser707Tyr) as the cause of a novel CD21 deficiency: Hypogammaglobulinemia autoinflammatory syndrome in 2 affected members of a family.48 CD21, the complement receptor type 2, is expressed on mature A father and his daughter both had epidermolysis bullosa–like B cells and follicular dendritic cells.61 In addition to binding the eruptions in infancy, interstitial pneumonitis, arthralgia, eye in- complement component C3d, CD21 also binds interferon a and flammation, enterocolitis, cellulitis, and recurrent sinopulmonary CD2362 and serves as the main cellular entry receptor for infections. Immunologic workup showed low circulating IgM/ EBV.63,64 CD21 forms a part of the CD19 complex, decreasing IgA levels and absence of class-switched memory B cells. The in- the threshold for antigen stimulation of B cells through the flammatory manifestations were refractory to treatment with non- BCR.65 A 28-year-old man presented with recurrent infections, steroidal anti-inflammatory drugs and TNF inhibitors but splenomegaly, hypogammaglobulinemia, and reduced class- 2 1 responsive to high-dose corticosteroids and, to a lesser extent, switched memory (IgD CD27 ) B-cell numbers but a normal to IL-1 blockade. B cells showed increased PLCg2-dependent antibody response to vaccine antigens.66 Compound heterozygous signaling after receptor cross-linking, as indicated by increased mutations in the CD21 gene prohibited CD21 receptor expression. levels of inositol trisphosphate production, intracellular Ca21 re- Functional studies showed a complete loss of costimulatory activ- lease, and extracellular signal-regulated kinase phosphorylation. ity of C3d in enhancing B-cell receptor stimulation. Vaccination In conclusion, a central role for PLCg in controlling Ca21 sig- response to pneumococcal polysaccharide vaccination was mod- naling and thus a plethora of cellular responses could explain the erately impaired, but the responses to protein antigens were various clinical features, with the involvement of the humoral preserved. The patient’s B cells were unable to bind to the immune system and various forms of inflammation as the common EBVgp350 antigen; however, the patient underwent EBV sero- theme. Allelic heterogeneity at the PLCG2 locus apparently further conversion in vivo, and his B cells were easily immortalized by contributes to the diversity of cellular and clinical phenotypes. EBV in vitro. This indicates that CD21 is not required for EBV infection in vitro and in vivo. The patient’s clinical condition improved on prophylactic antibiotics and intermittent gammaglobu- PREDOMINANTLY ANTIBODY DEFECTS lin substitution. CD21 deficiency shares many features with CD19 Defect in the p85a subunit of phosphoinositide and CD81 deficiency, although with less clinical severity.67,68 3-kinase: Agammaglobulinemia and absent B cells Preservation of specific antibody responses and normal responses Early B-cell development is under lineage-specific genetic to direct BCR stimulation in patients with CD21 deficiency prob- control. Genetic defects of Bruton tyrosine kinase and compo- ably contribute to this clinical variability.66 This case suggests that nents of the pre–B-cell receptor (BCR), such as the m heavy chain, patients with CD21 deficiency present with recurrent infections l5, Iga,Igb, and the downstream scaffold protein B-cell linker, and low serum IgG levels but uneventful EBV infection. have been described in more than 90% of patients with isolated defects in B-cell development and agammaglobulinemia.51 A report has recently described a homozygous premature stop LPS-responsive beige-like anchor deficiency: codon in PIK3R1, which encodes 3 regulatory subunits of phos- Hypogammaglobulinemia with autoimmunity and phoinositide 3-kinase (PI3K) by use of alternative splicing.52 early colitis The patient, a young woman with agammaglobulinemia and Linkage analysis and whole-exome sequencing conducted by 2 absent B cells, had early onset of infections and multiple groups led to the identification of homozygous, autosomal J ALLERGY CLIN IMMUNOL PARVANEH ET AL 319 VOLUME 131, NUMBER 2 recessive, LPS-responsive beige-like anchor (LRBA) gene muta- T, B, and NK cells.80,81 Two independent reports have recently tions in 10 patients from 5 unrelated families.69,70 The clinical described a similar presentation of abnormal adaptive human symptoms and laboratory findings in these patients were highly immunity and persistent EBV viremia attributed to CD27 defi- variable. Most had early onset of recurrent bacterial infections, ciency.82,83 Ten patients from 4 independent families (from autoimmune disease, or both. A subset had severe nonbloody Morocco, Turkey, and Lebanon) were confirmed to have homozy- diarrhea. One of the patients also had recurrent EBV-related lym- gous mutations in the gene encoding CD27. The clinical picture phoproliferative disease.69 Decreased serum IgG and IgA concen- varied from asymptomatic memory B-cell deficiency to persistent trations were seen in 8 of the 10 patients. CD191 B-cell counts symptomatic EBV viremia and malignant lymphoma. After EBV were variable, but switched memory B-cell counts were low in infection, hypogammaglobulinemia developed in 3 of the affected all patients who were tested. In addition, an increased susceptibil- subjects. T cell–dependent B-cell responses were abnormal,82 ity to apoptosis was documented in LRBA-deficient EBV immor- whereas antipolysaccharide antibodies were detectable.83 More- talized B cells.70 T cells were phenotypically normal, with over, CD81 T-cell function was disturbed, and invariant NK variable proliferative responses to mitogens and anti-CD3.69 T-cell numbers were diminished. Three patients died, 2 others The product of the LRBA gene (LRBA) is a cytosolic protein underwent successful allogeneic hematopoietic stem cell trans- expressed in many tissues believed to be involved in endocytosis plantations, and 2 received anti-CD20 therapy repeatedly. CD27 of ligand-activated receptors and also control of apoptosis.71,72 deficiency predisposes to symptomatic and potentially fatal The authors suggest that the autoimmune features seen in EBV infection and hypogammaglobulinemia, a phenotype that LRBA-deficient patients were attributable to increased apoptosis is similar to that of X-linked lymphoproliferative disease. and defective inhibitory receptor signaling.69,70 LRBA deficiency should be considered in the presence of early-onset hypogammaglobulinemia associated with colitis, autoimmune features, or CONGENITAL DEFECTS OF PHAGOCYTE NUMBER, both. The mechanism of disease remains to be deciphered. FUNCTION, OR BOTH Interferon-stimulated gene 15 deficiency: Mendelian susceptibility to mycobacterial diseases DEFECTS OF IMMUNE DYSREGULATION Mendelian susceptibility to mycobacterial diseases (MSMD) Pallidin deficiency: Hermansky-Pudlak syndrome predisposes subjects to severe disease on infection by weakly type 9 virulent mycobacteria, such as nontuberculous environmental Hermansky-Pudlak syndrome (HPS) subtypes present with mycobacteria and BCG. Germline mutations in 6 autosomal and 2 some degree of albinism and variable bleeding diathesis.73 How- X-linked genes involved in IFN-g–mediated immunity have been ever, some subtypes have additional features, such as neutropenia reported to cause MSMD (Fig 2).84-86 Recently, another genetic and defective lymphocyte-mediated cytotoxicity, as seen in HPS- cause of MSMD was described in 2 kindreds.87 Three children 2.74 Two recent articles reported the same homozygous nonsense from 2 distinct kindreds from Iran and Turkey presented with (c.232C>T) PLDN mutation in 2 unrelated patients with HPS-like BCG-induced clinical disease starting in early infancy and were phenotype.75,76 PLDN is mutated in the HPS mouse model pallid found to carry homozygous interferon-stimulated gene 15 (or HPS-9) and encodes the protein pallidin that interacts with the (ISG15) mutations.87 The clinical and immunologic phenotypes early endosomal t-SNARE syntaxin-13.77,78 of these patients resembled those of IL-12 receptor b1 defi- A 17-year-old Italian girl with partial albinism, nystagmus, and ciency,88 with impaired IFN-g immunity and relatively mild normal neurologic development presented with recurrent cutane- MSMD responsive to antimycobacterial therapy. In mice ISG15 ous infections.75 She had leukopenia and thrombocytopenia at pre- is induced by IFN-a/b, which is produced in response to viral in- sentation. NK cell degranulation and cytolysis were shown to be fection and has been shown to play a role in antiviral defense.89,90 defective.75 In addition, a 9-month-old Indian boy presented at However, it seems that the antiviral function of ISG15 is redun- birth with generalized hypopigmentation and respiratory distress dant in human subjects because the patients did not experience but no history of infections or cytopenias.76 Electron microscopy unusual viral infections. During phagocytosis, granulocytes are of platelets at 9 months showed absent platelet delta granules, a major source of ISG15 secretion.87 Free ISG15 then potentiates which is consistent with HPS. Neither of the patients had a bleed- the secretion of IFN-g, mostly by NK cells.91 ISG15 is therefore ing history, and results of platelet aggregation studies were nor- not only an IFN-a/b–inducible, intracellular, ubiquitin-like mol- mal.76 The clinical picture of the Italian patient was reminiscent ecule involved in ISGylation but also an IFN-g–inducing secreted of the accelerated phase of hemophagocytic lymphohistiocytosis, cytokine. This function complements the role of the IL-12–IFN-g a feature that was not substantiated in a pallid mouse model. The circuit in the control of mycobacterial infection. The IL-12–IFN-g milder clinical phenotype of the second case might be attributed to circuit involves mostly mononuclear phagocytes and T cells, his younger age. Identification of more patients with hemophago- whereas the ISG15–IFN-g circuit involves mostly granulocytes cytic lymphohistiocytosis presentation could list PLDN deficiency and NK cells. In granulocytes ISG15 was found to be expressed as a novel cause of albinism and immunodeficiency. in secretory granules. The mechanisms by which ISG15 stimu- lates NK and T cells are not yet known. CD27 deficiency: Immune dysregulation and persistent EBV infection DEFECTS IN INNATE IMMUNITY In clinical practice CD27 is recognized as a marker for memory NKX2-5 deficiency: Isolated congenital asplenia B cells and is used to subclassify patients with a variety of B-cell Congenital asplenia, which can be diagnosed based on the immunodeficiencies.79 After binding its natural ligand, CD70, results of ultrasonography or the presence of Howell-Jolly bodies CD27 regulates differentiation and cellular activity in subsets of in blood smears, is often associated with complex visceral defects 320 PARVANEH ET AL J ALLERGY CLIN IMMUNOL FEBRUARY 2013

FIG 2. Cross-talk between monocyte/macrophage cells and T/NK lymphocytes. Genes in the IL-12/IFN-g pathway are particularly important for protection against mycobacterial disease. IRF8 is an IFN-g–inducible transcription factor required for the induction of various target genes, including IL-12. The NF-kB essential modulator (NEMO) mutations in the LZ domain impair CD40-NEMO–dependent pathways. Some gp91phox mutations specifically abolish the respiratory burst in monocyte-derived macrophages. ISG15 is secreted by neutrophils and potentiates IFN-g production by NK/T cells. Genetic defects that preclude monocyte development (eg, GATA2) can also predispose to mycobacterial infections (not shown). Mutant molecules in patients with unusual susceptibility to infection are indicated in red. IFNgR, IFN-g receptor; IL-12R, IL-12 receptor; MB, mycobacterium; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2. as part of heterotaxy syndromes.92,93 The causative mutations emerged as the major player in localized immunity against herpes have been identified in various genes controlling left-right lateral- simplex virus in the central nervous system.104,105 A recent study ity.94,95 In contrast, isolated congenital asplenia (ICA; ie, in the of patients with HSE explored the Toll/IL-1 receptor domain– absence of heterotaxy or cardiac anomalies) was first thought to containing adaptor inducing IFN-b (TRIF) protein as another be rare and sporadic.96 Studies of case reports and rare national component of the TLR3 antiviral pathway.106 Two patients with surveys suggested probable autosomal dominant, as well as spon- HSE with TRIF deficiency were identified, one with a homozy- taneous, occurrences.97,98 The most frequent pathogens in gous nonsense mutation, resulting in complete recessive TRIF patients with ICA are encapsulated bacteria, with Streptococcus deficiency, and another with a heterozygous missense mutation, pneumonia as the leading infectious agent.98,99 The infections leading to partial dominant (probably by negative dominance) associated with ICA can be fatal in childhood but tend to improve TRIF deficiency. TRIF is an adaptor protein serving as the sole with age.98 Using mouse models of spleen morphogenesis to help adaptor to TLR3 and as an alternative adaptor through TRIF- focus the exome sequencing data of a family with ICA led to the related adaptor molecule to TLR4.107,108 Once activated by discovery of a heterozygous missense mutation in NKX2-5.100 agonist-induced TLR3 dimerization, TRIF activates downstream Pbx1, a prime regulator of the organogenesis of the spleen, gov- signaling events, culminating in production of IFN-a/b, IFN-l, erns spleen development through transactivation of the Nkx2-5 and proinflammatory cytokines.109,110 TRIF-deficient patients’ gene product (Nkx-2).101 Moreover, both Pbx1 and Nkx-2 control fibroblasts did not produce interferons after stimulation with spleen growth by repression of CDK inhibitor p15Ink4b.102 Mice TLR3 agonists and showed increased susceptibility to HSV1 deficient for Pbx/Nkx2-5/p15 components exhibit disrupted infections in vitro.106 spleen development.100 Finding of a NKX2-5 mutation as a possi- Another study also brings to light new facts about genetic ble cause of human ICA reinforces the central role of PBX target susceptibility to HSE. Two different heterozygous missense genes in the development of spleen. This study also paves the way mutations in TANK-binding kinase 1 (TBK1) were identified as for the investigation of ICA in other kindreds. causing HSE in 2 patients from Poland and France.111 TBK1 encodes TBK1, a noncanonical IkB kinase of the NF-kB signaling pathway, which controls the activity of transcription factors of Toll/IL-1 receptor domain–containing adaptor the interferon regulatory factor family, mainly interferon regula- inducing IFN-b and TANK-binding kinase tory factor 3.112 Through this process, TBK1 exerts its antiviral 1 deficiencies: Herpes simplex encephalitis role through regulation of the production of multiple interferons. Herpes simplex virus 1 (HSV1) is an ubiquitous pathogen that Both mutant TBK1 alleles were loss-of-function mutations under- causes acute, self-limiting infection after primary exposure. lying an autosomal dominant trait in heterozygous patients by However, it can trigger debilitating and fatal herpes simplex haploinsufficiency (D50A) or negative dominance (G159A).111 virus encephalitis (HSE) on rare occasions.103 Thanks to recent TLR3-related antiviral activities were blunted in both mutant fi- studies, the Toll-like receptor 3 (TLR3)–interferon pathway broblasts; however, the defects were rescued by IFN-a2b. The J ALLERGY CLIN IMMUNOL PARVANEH ET AL 321 VOLUME 131, NUMBER 2 elucidation of TRIF and TBK1 deficiencies substantiates the widespread, diffuse erythematous pustular rash associated with obligatory role of the TLR3 pathway in immunity against high fever, malaise, and leukocytosis.125,126 By using homozy- HSV1 in the central nervous system and its redundancy for pro- gosity mapping and exome sequencing, a total of 19 patients tective immunity otherwise. were found to have homozygous or compound heterozygous mutations in the IL36RN gene, encoding IL-36 receptor antagonist (IL-36Ra).127,128 IL-36Ra (also known as IL-1F5) is an antagonist Minichromosome maintenance complex of 3 cytokines of the IL-1 family (IL-36A, IL-36B, and IL-36G) component 4 deficiency: NK cell deficiency that have NF-kB– and mitogen-activated protein kinase–activat- associated with growth retardation and adrenal ing properties.129,130 Defective expression and function of IL- insufficiency 36Ra thus could direct uncontrolled inflammatory processes on NK cells are cells of the innate immune system that exert pathogen stimulation through mucosal surfaces. Generalized pus- antiviral and antitumor surveillance functions in mice.113 Some tular psoriasis provides one more example that highlights the cen- cases of selective quantitative circulating human NK cell defi- tral role of IL-1 signaling in tissue inflammation,131 illuminating a ciencies with specific susceptibility to viral infections have rational target for its treatment.132 been reported.114-117 However, the mechanisms that control NK cell development in human subjects remain unclear. Two groups CONCLUSION of researchers have shown that human NK cell deficiency is The field of PIDs is advancing at full speed in 2 directions. New caused by a homozygous mutation in the minichromosome main- genetic causes of known PIDs are being discovered (eg, CD21 and tenance complex component 4 (MCM4) gene in patients from the 118,119 TRIF). Moreover, new phenotypes qualify as PIDs with the Irish traveler community. In addition, patients with NK cell identification of a first genetic cause (eg, generalized pustular deficiency displayed growth retardation, increased chromosomal psoriasis). Recent findings contribute fundamental knowledge breakage, adrenal insufficiency, and, in 1 case, lymphoma. From about immune system biology and its perturbation in disease. They an infectious perspective, the patients had unusual susceptibility 118 are also of considerable clinical benefit for the patients and their to herpes viruses. The studied patients shared the same splice families. A priority is to further translate these new discoveries into defect, probably because of a founder effect. MCM4 is a highly improved diagnostic methods and more effective therapeutic conserved DNA helicase that is required for DNA replication strategies, promoting the well-being of patients with PIDs. and cell proliferation.120 Patients’ fibroblasts contained high 118 numbers of DNA breaks and showed cell-cycle abnormalities. 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